Significant increases in the occurrence of cases of aspergillosis have occurred since the first reported case of invasive aspergillosis in 1953 (Rankin, N E (1953) Br. Med. J. 183: 918-919; reviewed in Denning, D W (1998) Clin. Infect. Dis. 26: 781-803). This increase correlates with the increasing numbers of immunocompromised patients, including AIDS (Acquired Immune Deficiency Syndrome) and organ transplant patients taking immunosuppressant drugs to prevent organ rejection. Although Aspergillus is generally considered an opportunistic pathogen, invasive aspergillosis has been documented from immunocompetent patients as well (Denning D W, Stevens D A (1990) Rev. Infect. Dis. 12: 1147-1202; Bodey G P, Vartivarian S (1989) Eur. J. Clin. Microbiol. Infect. Dis. 8: 413-437). Aspergillus species causes a wide spectrum of disease conditions ranging from superficial cutaneous infections to life-threatening systemic mycoses. Mortality rates can approach 100% in invasive aspergillosis (Denning D W (1996) Clin. Infect. Dis. 23 608-615) However, only a few species of the fungal genus Aspergillus are found as human pathogens (Denning, D W (1998) Clin. Infect. Dis. 26: 781-803) and A. fumigatus is among the most common of these. A. fumigatus is a soil-borne fungus typically associated with decaying organic matter (Mullins J, Harvey R, Seaton A. (1976) Clin. Allergy 6: 209-217) although it is likely that is ubiquitous in the environment due to the airborne distribution of its spores. A Southern hybridization study of the genetic diversity of A. fumigatus isolates from both clinical specimens and from the environment suggests that most if not all strains of A. fumigatus are capable of becoming opportunistic pathogens (Debeaupuis J P et al (1997) Infect. Immun. 65: 3080-3085). Potential allergen-encoding genes in A. fumigatus have been isolated using M13 phage display and screening with IgE from patients allergic to A. fumigatus (Crameri R et al (1998) Int. Immunol. 10: 1211-1216; Crameri R (1998) Int. Arch. Allergy Immunol. 115: 99-114; Crameri R, Blaser K (1996) Int. Arch. Allergy Immunol. 110: 41-45).
A number of molecules have been suggested to have a role in virulence. A. fumigatus produces a number of extracellular toxins, such as gliotoxin (Mullbacher A, Eichner R D (1984) Proc. Natl. Acad. Sci. U.S.A. 81: 3835-3837; Mullbacher A, Waring P, Eichner R D (1985) J. Gen. Microbiol. 131: 1251-1258 and restrictocin (Lamy B, Davies J (1991) Nucl. Acids Res. 19: 1001-1006; Lamy B, Moutaouakil M., Latge J, and Davies J (1991) Mol. Microbiol. 5: 1811-1815). In a mouse model, however, deletions of the A. fumigatus restrictocin toxin gene had no effect on virulence relative to the wild type gene (Smith J M, Davies J E, Holden D W (1993) Mol. Microbiol. 9:1071-1077; Holden D W, Tang C M, Smith J M (1994) Antonie van Leeuwenhoek 65: 251-255). Gliotoxin is known to act as an immunosuppressant in vivo (Sutton P, Newcombe N R, Waring P, Mullbacher A (1994) Infect. Immun. 62: 1192-1198) possibly through the inhibition of the activation of the transcription factor NF-kappaB (Pahl H L et al (1996) J. Exp. Med. 183: 1829-1840), but its role in pathogenesis is still unproven (Waring P, Mullbacher A (1994) Infect. Immun. 62: 1192-1198). Additional toxins are known from A. fumigatus (Moss M O (1994) in Powell K A, Perberdy J F, and Renwick A, editors. The genus Aspergillus. New York. Plenum Press. pp. 29-50).
Additional potential virulence factors have been suggested, including extracellular proteases (reviewed in Denning, D W (1998) Clin. Infect. Dis. 26: 781-803). However, deletion of AFA1, an extracellular alkaline protease with elastase activity, had no effect on pathogenicity (Holden D W, Tang C M, and Smith J M (1994) Antonie van Leeuwenhoek 65: 251-255). Genes encoding ATP-binding cassette proteins (AfuMDR1 and AfuMDR2) have been isolated from A. fumigatus using degenerate PCR primers (Tobin M B, Peery R B, Skatrud P L (1997) Gene 200: 11-23). These proteins have similarities to multiple drug resistance genes from other organisms. Increased resistance to two antifungal agents was observed when the AfuMDR1 gene was expressed in S. cerevisiae. 
Only two antifungals, itraconazole and amphotericin B, are currently used to treat invasive aspergillosis (Denning D W (1998) Clin. Infect. Dis. 26: 781-803). Fluconazole, which is effective against other fungal infections including those of Candida albicans, is ineffective against Aspergillus clinical isolates (Dermoumi H (1994) Chemotherapy 40: 92-98). Isolates of Aspergillus fumigatus resistant to itraconazole have been reported (Denning D W et al (1997) Antimicrob. Agents Chemother. 41: 1364-1368). Resistance to amphotericin B after itraconazole therapy (Schaffner A, Bohler A (1993) Mycoses 36: 421-424) has also been reported and this is not due to direct antagonism between the drugs as the itraconazole treatment was stopped prior to amphotericin B treatment. In vitro studies demonstrate that amphotericin B-resistant strains can be readily produced in the laboratory (Manavathu E K, Alangaden G J, Chandrasekar P H (1998) J. Antimicrob. Chemother. 41:615-619) and in vivo resistance of A. fumigatus to amphotericin B in mice has been demonstrated (Verweij P E (1998) Antimicrob. Agents Chemother. 42: 873-878).
The severity and difficulty in diagnosing A. fumigatus infections, the limited number of effective antifungals for treatment of infections, and the development of antifungal-resistant A. fumigatus strains provide the rationale for the identification of targets for more rapid and effective methods of identification, prevention, and treatment of aspergillosis. The elucidation of the genome of A. fumigatus would enhance the understanding of how A. fumigatus, as well as other fungi, causes invasive disease and how best to combat fungal infection.